Practice Update: Oncology

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The BRCA1ness Signature
is Associated Significantly
With Response to PARP
Inhibitors in the I-SPY 2
Randomized Neoadjuvant
Setting
Breast Cancer Research
Take-home message
• In this study, a diagnostic gene expression signature
was created using 128 triple-negative breast cancer
samples and tested in 116 HER2-negative patients to
determine the association between pathologic com-
plete response and BRCA1ness in patients receiving
veliparib–carboplatin combined with standard chemo-
therapy compared with patients receiving standard
chemotherapy alone. BRCA1ness was significantly
associated with response to veliparib–carboplatin but
not to standard chemotherapy.
• In the I-SPY 2 neoadjuvant setting, the BRCA1ness sig-
nature predicted the benefit of veliparib–carboplatin
combined with standard chemotherapy compared with
standard chemotherapy alone.
Abstract
BACKGROUND Patients with BRCA1-like tumors correlate with improved
response to DNA double-strand break-inducing therapy. A gene
expression-based classifier was developed to distinguish between
BRCA1-like and non-BRCA1-like tumors. We hypothesized that these
tumors may also be more sensitive to PARP inhibitors than standard
treatments.
METHODS A diagnostic gene expression signature (BRCA1ness) was
developed using a centroid model with 128 triple-negative breast
cancer samples from the EU FP7 RATHER project. This BRCA1ness
signature was then tested in HER2-negative patients (n= 116) from the
I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in com-
bination with carboplatin (V-C), or standard chemotherapy alone. We
assessed the association between BRCA1ness and pathologic com-
plete response in the V-C and control arms alone using Fisher’s exact
test, and the relative performance between arms (biomarker × treat-
ment interaction, likelihood ratio p<0.05) using a logistic model and
adjusting for hormone receptor status (HR).
RESULTS We developed a gene expression signature to identify BRCA1-
like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature
associated significantly with response to V-C (p=0.03), but not in the
control arm (p=0.45). We identified a significant interaction between
BRCA1ness and V-C (p=0.023) after correcting for HR.
CONCLUSIONS A genomic-based BRCA1-like signature was success-
fully translated to an expression-based signature (BRC1Aness). In
the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness
signature is capable of predicting benefit of V-C added to standard
chemotherapy compared to standard chemotherapy alone.
The BRCA1ness signature is associated significantly with response
to parp inhibitor treatment versus control in the I-SPY 2 randomized
neoadjuvant setting. Breast Cancer Res 2017 Aug 25;[EPub Ahead
of Print], TM Severson, DM Wolf, C Yau, et al.
tissue of 2 mm or more, were recruited. Patients were randomly assigned
(1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-
breast radiotherapy and 40 Gy to the partial breast (reduced-dose group),
or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment
fractions. Computer-generated random permuted blocks (mixed sizes of
six and nine) were used to assign patients to groups, stratifying patients
by radiotherapy treatment centre. Patients and clinicians were not masked
to treatment allocation. Field-in-field intensity-modulated radiotherapy was
delivered using standard tangential beams that were simply reduced in
length for the partial-breast group. The primary endpoint was ipsilateral
local relapse (80% power to exclude a 2•5% increase [non-inferiority mar-
gin] at 5 years for each experimental group; non-inferiority was shown if
the upper limit of the two-sided 95% CI for the local relapse hazard ratio
[HR] was less than 2•03), analysed by intention to treat. Safety analyses
were done in all patients for whom data was available (ie, a modified inten-
tion-to-treat population).
FINDINGS Between May 3, 2007, and Oct 5, 2010, 2018 women were
recruited. Two women withdrew consent for use of their data in the anal-
ysis. 674 patients were analysed in the whole-breast radiotherapy (control)
group, 673 in the reduced-dose group, and 669 in the partial-breast
group. Median follow-up was 72•2 months (IQR 61•7-83•2), and 5-year
estimates of local relapse cumulative incidence were 1•1% (95% CI 0•5-
2•3) of patients in the control group, 0•2% (0•02-1•2) in the reduced-dose
group, and 0•5% (0•2-1•4) in the partial-breast group. Estimated 5-year
absolute differences in local relapse compared with the control group
were -0•73% (-0•99 to 0•22) for the reduced-dose and -0•38% (-0•84
to 0•90) for the partial-breast groups. Non-inferiority can be claimed for
both reduced-dose and partial-breast radiotherapy, and was confirmed
by the test against the critical HR being more than 2•03 (p=0•003 for the
reduced-dose group and p=0•016 for the partial-breast group, compared
with the whole-breast radiotherapy group). Photographic, patient, and
clinical assessments recorded similar adverse effects after reduced-dose
or partial-breast radiotherapy, including two patient domains achieving
statistically significantly lower adverse effects (change in breast appear-
ance [p=0•007 for partial-breast] and breast harder or firmer [p=0•002
for reduced-dose and p<0•0001 for partial-breast]) compared with whole-
breast radiotherapy.
INTERPRETATION We showed non-inferiority of partial-breast and reduced-
dose radiotherapy compared with the standard whole-breast radiotherapy
in terms of local relapse in a cohort of patients with early breast cancer,
and equivalent or fewer late normal-tissue adverse effects were seen.
This simple radiotherapy technique is implementable in radiotherapy
centres worldwide.
Partial-breast radiotherapy after breast conservation surgery for patients
with early breast cancer (UK IMPORT LOW Trial): 5-year results from a
multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet
2017 Aug 02;[EPub Ahead of Print], CE Coles, CL Griffin, AM Kirby, et al.
EDITOR’S PICKS 7
VOL. 1 • NO. 3 • 2017